Among the most important issues in biogerontology today is an understanding of the mechanisms that underlie lifespan extension associated with reduced activity in the insulin/IGF-I signaling pathway. Whereas single mutations in the IGF-I receptor and signaling pathways impart lifespan extension in Caenorhabditis elegans and Drosophila melanogaster, the most robust examples of lifespan extension in mammals are associated with reductions in both IGF-I and growth hormone. Mouse models exhibiting deficiency in pituitary development or growth hormone production and/or signaling show decreased IGF-I levels and a dramatic increase in lifespan. Against a backdrop of growth hormone deficiency, however, it is impossible to attribute the effect on lifespan in these animals solely to reductions in IGF-I, excluding a potentially distinct role for growth hormone in mammalian lifespan modulation. Mouse lines which exhibit reduced IGF-I signaling show much smaller increases in lifespan suggesting that IGF-I suppression alone may not be sufficient to produce the robust lifespan extension seen in animals which lack both growth hormone and IGF-I. However, current models do not provide the tools necessary to define the roles that IGF-I and growth hormone play in modulating longevity in mammals. We propose to create novel mouse models, exhibiting growth hormone independent production of IGF-I. We will perform a characterization of these mice in terms of IGF-I production, development, metabolism, bone growth and lifespan. If we find a major influence of GH on longevity independent of IGF-I, the results of these studies would pave the way for a paradigm shift in our thinking regarding the influence of IGF-I and longevity. PUBLIC HEALTH RELEVANCE: The work proposed in this application will create new mouse line that do not produce growth hormone but will produce one of the primary targets of growth hormone, known as the Insulin-like growth factor type 1. These mice will be used to evaluate the relative contribution of these hormones to late life changes and lifespan. The studies will provide insight into potential therapeutic uses for these hormones in the elderly.